Our group has focused on pharmacologic manipulation of fetal hemoglobin levels in patients with genetic defects of hemoglobin. We have previously shown that hydroxyurea (HU) treatment of severely affected sickle cell patients results in about a 70 to 75% response rate defined by at least a two-fold increase in F-reticulocytes and a concomitant two-fold rise in per cent in hemoglobin F. The best responding patients achieved levels of fetal hemoglobin of 10 to 15%. We have subsequently treated 6 patients with beta thalassemia intermedia with HU. Two patients showed an increase of at least 2-fold in HbF levels and of 5-fold in gamma globin mRNA. Curiously, two other patients showed an obvious increase primarily in beta- globin biosynthesis corresponding to an increase in beta-mRNA transcripts without a change in gamma globin synthesis. Thus, in addition to its effects in stimulating gamma globin synthesis, HU may be useful in the context of treatment of beta thalassemia through other mechanisms. In an effort to achieve higher levels of hemoglobin F, in a more pancellular distribution, we have recently treated four patients with sickle cell disease who were receiving hydroxyurea for periods of 5-15 months on four consecutive days with escalating dose of recombinant erythropoietin (EPO) for 7 weeks, given on the alternate three days along with oral iron sulfate. Treatment with EPO in combination with chronic hydroxyurea therapy had a significant effect on the percentage of hemoglobin F containing reticulocytes (F-reticulocytes), and red cells (F-cells) and on the total hemoglobin F level. In these four patients such combination therapy was associated with a 1.4 to 3 fold increase in F-reticulocytes, a 1.3 to 2 fold increase in F-cells and a 1.4 to 2 fold increase in the percentage of hemoglobin F when compared to the maximal values previously achieved on hydroxyurea alone. In addition, in contrast to the results on hydroxyurea alone, treatment with combination HU/EPO resulted in maximal stimulatory effects within ten to twelve days of therapy. This additional augmentation resulted in a further decrease in serum bilirubin and lactate dehydrogenase as well as a further decline in intracellular hemoglobin S polymerization tendency at physiologic oxygen saturation in cells containing fetal hemoglobin. We conclude that (1) while HU is a potent inducer of gamma-globin synthesis, it may have a more generic effect on globin gene expression; (2) when given in an alternating fashion with erythropoietin in addition to iron supplementation it tends to augment the fetal hemoglobin responses seen with hydroxyurea alone.